Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance

Abstract

Please cite this paper as: McKimm‐Breschkin (2012) Influenza neuraminidase inhibitors: Antiviral action and mechanisms of resistance. Influenza and Other Respiratory Viruses 7(Suppl. 1), 25–36.There are two major classes of antivirals available for the treatment and prevention of influenza, the M2 inhibitors and the neuraminidase inhibitors (NAIs). The M2 inhibitors are cheap, but they are only effective against influenza A viruses, and resistance arises rapidly. The current influenza A H3N2 and pandemic A(H1N1)pdm09 viruses are already resistant to the M2 inhibitors as are many H5N1 viruses. There are four NAIs licensed in some parts of the world, zanamivir, oseltamivir, peramivir, and a long‐acting NAI, laninamivir. This review focuses on resistance to the NAIs. Because of differences in their chemistry and subtle differences in NA structures, resistance can be both NAI‐ and subtype specific. This results in different drug resistance profiles, for example, the H274Y mutation confers resistance to oseltamivir and peramivir, but not to zanamivir, and only in N1 NAs. Mutations at E119, D198, I222, R292, and N294 can also reduce NAI sensitivity. In the winter of 2007–2008, an oseltamivir‐resistant seasonal influenza A(H1N1) strain with an H274Y mutation emerged in the northern hemisphere and spread rapidly around the world. In contrast to earlier evidence of such resistant viruses being unfit, this mutant virus remained fully transmissible and pathogenic and became the major seasonal A(H1N1) virus globally within a year. This resistant A(H1N1) virus was displaced by the sensitive A(H1N1)pdm09 virus. Approximately 0·5–1·0% of community A(H1N1)pdm09 isolates are currently resistant to oseltamivir. It is now apparent that variation in non‐active site amino acids can affect the fitness of the enzyme and compensate for mutations that confer high‐level oseltamivir resistance resulting in minimal impact on enzyme function.

The significance of naturally occurring neuraminidase quasispecies of H5N1 avian influenza virus on resistance to oseltamivir: a point of concern

“…Upon detailed examination by various authors it was discovered that non-active site residues have subtle but important effects on the activity and level of expression of the NA enzyme (Baranovich et al, 2011;McKimm-Breschkin, 2013). For example, the V234M and R222Q mutations help to decrease NA folding and transport defects by increasing the amount of NA reaching the cell surface and thus compensate for the active site mutation H274Y (Baranovich et al, 2011).…”

Transmission of avian influenza A(H7N9) virus from father to child: a report of limited person-to-person transmission, Guangzhou, China, January 2014

“…In accord with the NA (neuraminidase) sequencing data, testing of the A/Anhui/1/2013 virus in the neuraminidase inhibition assay indicates that this virus is susceptible to neuraminidase inhibitor antiviral drugs oseltamivir and zanamivir (CDC 2013b) (Tables 3a and 3b). The arginine (R) to lysine (K) substitution at residue 292 (N2 numbering), which is likely to diminish efficacy of oseltamivir and zanamivir (McKimm-Breschkin 2013, Gubareva et al 1997 (Tables 3a and 3b), was detected initially in the A/Shanghai/1/2013 virus ). However, testing of A/Shanghai/1/2013 virus in the neuraminidase inhibition assay generated discrepant results, which may be attributed to a mixture of R and K at 292 residue of the virus (Table 3b).…”

Current perspectives on applications of shikimic and aminoshikimic acids in pharmaceutical chemistry

“…Many mutations conferring reduced sensitivity to OSP (His 274 Tyr, Glu 119 Val, and Arg 292 Lys) cluster around the hydrophobic pocket, impairing Glu 276 rotation. 47 …”

“…10,47 Therefore, the high demand for this drug is not adequately met by industrial production using SA, which was developed by Gilead (Gilead Sciences Inc., Foster City, CA, USA) and Roche (Hoffman-La Roche Ltd., Basel, Switzerland) chemists; notably, the current supply of Tamiflu ® covers just 2% of the world population. 49 To protect people from pandemic human or H5N1 avian influenza, OSP should be manufactured and stocked in every country worldwide.…”